Neural progenitor cells maintain a tight control of the balance between self-renewal and differentiation in the developing and adult brains and can respond to environmental cues to either switch on more proliferation or produce more differentiated cells. Such a homeostatic control is not only important for normal development but also critical for proper functioning of the brain. The long-term goal of our study is to understand how self- renewal and differentiation are regulated during brain development and to apply the obtained knowledge for developing better diagnostic tools and novel therapeutic approaches for treating developmental brain disorders and brain cancers. This application proposes to investigate a novel protein interaction network that is crucial for controlling symmetric (self-renewal) versus asymmetric (differentiation) cell division in neural progenitor cells. In our previous studies, we have demonstrated, using combined cellular, embryological, and genetic approaches, that the regulator of G protein signaling (RGS)-mediated ephrin-B reverse signaling pathway is essential for maintaining the neural progenitor cell state in the embryonic cerebral cortex and that the Ga subunit signaling pathway is important for activating neuronal differentiation. We have identified a mitotic kinesin that can interact with and recruit the ephrin B/RGS proteins into the midbody of dividing neural progenitor cells, suggesting that the role of the ephrin-B/RGS pathway in neural progenitor cell regulation is linked to cytokinesis, the final stage of cell division. In addition, we have recently identified several interacting proteins of th active Ga subunits and found that these proteins, similar to G? subunit, could activate neurogenesis. We thus propose to further characterize the biochemical interaction of the ephrin-B/RGS/mitotic kinesin and Ga subunit interaction network and examine the potential function of these networks in shaping neural progenitor cells' decision to either divide symmetrically or asymmetrically. We anticipate that the data obtained from this study will ultimately help understand what and how molecular interactions in neural progenitor cells guides the balance between self-renewal and differentiation and how dysregulation in these networks may lead to certain developmental brain disorders or tumorigenesis.